The present invention relates to compounds of Formula (I) depicted hereinbelow, which compounds are xcex23 adrenergic receptor agonists and, accordingly, have utility as, inter alia, hypoglycemic, and anti-obesity agents.
The invention further relates to intermediates useful in the preparation of the compounds of Formula (I); to combinations of the compounds of Formula (I) with anti-obesity agents; to pharmaceutical compositions comprising such compounds and combinations; and to methods of using the compounds, combinations, and pharmaceutical compositions in the treatment of xcex23 adrenergic receptor-mediated diseases, conditions, or disorders in a mammal. The compounds and combinations of the invention also possess utility for increasing the content of lean meat in edible animals, i.e. ungulate animals such as cattle, swine, and the like, as well as poultry.
The compounds and combinations of this invention further possess utility in the treatment of intestinal motility disorders, depression, prostate disease, dyslipidemia, and airway inflammatory disorders.
The disease diabetes mellitus is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The results of these defects include, inter alia, elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin, the hormone that regulates carbohydrate utilization. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated, levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most Type 2 diabetic patients are also obese.
The compounds of the invention effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
Obesity constitutes a major health risk that leads to mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia. In the United States, more than 50% of the adult population is overweight, and almost 25% of the population is considered to be obese. The incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. Furthermore, obesity is a devastating disease which can also wreak havoc on an individual""s mental health and self-esteem, which can ultimately affect a person""s ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on society in general, much effort has been expended in efforts to treat obesity, however, success in the long-term treatment and/or prevention thereof remains elusive.
The compounds, pharmaceutucal compositions, and combinations of the invention also reduce body weight or decrease weight gain when administered to a mammal. The ability of the compounds to affect weight gain is due to activation of xcex23 adrenergic receptors which stimulate the metabolism of adipose tissue.
xcex2-Adrenergic agents have been generally classified into xcex21, xcex22, and xcex23 receptor-specific subtypes. Agonists of xcex2-receptors promote the activation of adenyl cyclase. Activation of xcex21 receptors invokes an increase in heart rate while activation of xcex22 receptors induces smooth muscle tissue relaxation which produces a drop in blood pressure and the onset of skeletal muscle tremors. Activation of xcex23 receptors is known to stimulate lipolysis (e.g., the breakdown of adipose tissue triglycerides into glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting the loss of fat mass. Accordingly, compounds that stimulate xcex23 receptors are therefore useful as anti-obesity agents, and can be further used to increase the content of lean meat in edible animals. In addition, compounds that are xcex23 receptor agonists have hypoglycemic activity, however, the precise mechanism of this effect is presently unknown.
Until recently, xcex23 adrenergic receptors were thought to be found predominantly in adipose tissue, however, xcex23 receptors are now known to be located in such diverse tissues as the intestine, (J. Clin. Invest., 91, 344 (1993)) and the brain Eur. J. (Pharm., 219, 193 (1992)). Stimulation of xcex23 receptors has also been demonstrated to induce relaxation of smooth muscle in the colon, trachea, and bronchi. See, for example, Life Sciences, 44, 1411 (1989), Br. J. Pharm., 112, 55 (1994), and Br. J. Pharmacol., 110, 1311 (1993). Furthermore, stimulation of xcex23 receptors has also been found to induce relaxation of histamine-contracted guinea pig ileum. See, for example, J. Pharm. Exp. Ther., 260, 1, 192 (1992).
The xcex23 receptor is also expressed in the human prostate (J. Clin. Invest., 91, 344 (1993). Because stimulation of the xcex23 receptor causes relaxation of smooth muscles that have been shown to express the xcex23 receptor, i.e. intestinal smooth muscle, one of ordinary skill in the art would also predict relaxation of prostate smooth muscle. Therefore, xcex23 agonists are useful in the treatment or prevention of prostate disease.
Commonly assigned U.S. Pat. No. 5,977,124 discloses certain xcex23 adrenergic receptor agonists having utility in the treatment of, inter alia, hypoglycemia and obesity.
U.S. Pat. No. 5,776,983 discloses certain catecholamines useful as xcex23-agonists.
U.S. Pat. No. 5,030,640 discloses certain a-heterocyclic ethanol amino alkyl indoles, which are useful as growth promoters, bronchodilators, anti-depressants, and anti-obesity agents.
U.S. Pat. No. 5,019,578 discloses certain a-heterocyclic ethanolamines useful as growth promoters.
U.S. Pat. No. 4,478,849 discloses pharmaceutical compositions comprising certain ethanolamine derivatives and methods of using such compositions in the treatment of obesity and/or hyperglycaemia.
U.S. Pat. No. 4,358,455 discloses certain heterocyclic compounds of the structural formula Het-CHOHxe2x80x94CH2xe2x80x94NH-aralkyl, which compounds are useful for treating glaucoma and cardiovascular disease.
European Patent Application Publication No. 0 516 349, published Dec. 2, 1992, discloses certain 2-hydroxyphenethyl amines which possess anti-obesity, hypoglycemic, and related utilities.
U.S. Pat. No. 5,153,210 discloses certain heterocyclic compounds of the formula ROxe2x80x94Xxe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R1)xe2x80x94C(R2)(R3)xe2x80x94(CH2)nxe2x80x94Yxe2x80x94Axe2x80x94R4xe2x80x94R5 which compounds are useful as anti-obesity and anti-hyperglycaemic agents.
PCT International Patent Application Publication No. WO 99/65877, published Dec. 23, 1999, discloses heterocyclic compounds having the structural formula 
which compounds are useful for the treatment of diseases susceptible to amelioration by administration of an atypical beta-adrenoceptor agonist.
The instant invention provides xcex23 adrenergic receptor agonists of structural Formula (I), 
the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, wherein Ar, R, R1, R2, R3, R4, R5, R6, R7, R8, X, and Y are as defined hereinbelow.
In another aspect, the invention provides intermediates useful in the preparation of the compounds of Formula (I); to combinations of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, with anti-obesity agents; to pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, or pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, and anti-obesity agents; and methods of treating xcex23 adrenergic receptor-mediated diseases, conditions, or disorders in a mammal which methods comprise administering to the mammal an effective amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutical composition thereof; or a combination of a compound of Formula (I), a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and an anti-obesity agent, or a pharmaceutical composition thereof acceptable salt of the compound, stereoisomer, or prodrug, and an anti-obesity agent, or a pharmaceutical composition thereof.
The present invention provides xcex23 adrenergic receptor agonists of structural Formula (I), 
the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, wherein:
Ar is pyridyl, oxazolyl, thiazolyl, or phenyl;
R is hydrogen, hydroxy, oxo, halogen, xe2x80x94CF3, xe2x80x94(C1-C6)alkyl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C3-C8)xyxloalkyl, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94NR9COR10, or xe2x80x94SO2R9;
R1 is hydrogen, xe2x80x94(C1-C6)alkyl, halogen, xe2x80x94(C1-C6)alkoxy, or hydroxy;
R2, R3, R4are, independently, hydrogen, or xe2x80x94(C1-C6)alkyl;
R5 is a 5- or 6-membered ring heterocycle having from 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen;
R6 and R7 are, independently, hydrogen, halogen, cyano, oxo, xe2x80x94(C1-C6)acyl, xe2x80x94CO2R9, xe2x80x94NR9R10, hydroxy, xe2x80x94(C1-C6)alkoxy, xe2x80x94CONR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, or xe2x80x94SO2R9; xe2x80x94(C1-C6)alkyl, optionally substituted with xe2x80x94(C3-C8)cycloalkyl, halogen, aryl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)haloalkyl, alkylalkoxy, hydroxy, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, xe2x80x94SO2R9, or heterocycle; xe2x80x94(C3-C8)cycloalkyl, optionally substituted with xe2x80x94(C1-C6)alkyl, xe2x80x94(C3-C8)cycloalkyl, halogen, aryl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)haloalkyl, alkylalkoxy, hydroxy, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, xe2x80x94SO2R9, or heteroxyxle; aryl, optionally substituted with xe2x80x94(C1-C6)alkyl, xe2x80x94(C3-C7)cycloalkyl, halogen, aryl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)haloalkyl, alkylalkoxy, hydroxy, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, xe2x80x94SO2R9, or heterocycle, optionally substituted with xe2x80x94(C1-C6)alkyl, xe2x80x94(C3-C8)cycloalkyl, halogen, aryl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)haloalkyl, alkylalkoxy, hydroxy, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, xe2x80x94SO2R9, or heterocycle;
R8 is hydrogen, xe2x80x94(C1-C4)alkyl, or halogen; and
R9 and R10 are, independently, hydrogen, xe2x80x94(C1-C6)alkyl, alkylalkoxy, xe2x80x94(C3-C8)cycloalkyl, xe2x80x94(C1-C6)haloalkyl, xe2x80x94(C1-C6)alkoxy, aryl, or heterocycle;
X is a direct bond or oxygen; and
Y is a direct bond, xe2x80x94(C1-C6)alkyl, xe2x80x94OCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, or oxygen; provided that:
(i) when Ar is phenyl, R is xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, or xe2x80x94SO2R9; and
(ii) when Ar is phenyl, xe2x80x94NR9SO2R10, and R6 and R7 are both hydrogen, then R5 is not imidazolyl.
The compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, wherein Ar, R, R1, R2, R3, R4, R5, R6, R7, R8, X, and Y are as defined hereinabove, that are extant in the (R)-stereoconfiguration, designated by Formula (Ixe2x80x2) hereinbelow, are especially preferred. 
A first generally preferred subgroup of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, comprises those compounds wherein Ar is pyridyl; R, R1, R2, R3, R4 and R8, are hydrogen; X is oxygen; Y is a direct bond; and R5 is a five- or six-membered ring heterocycle selected from the group consisting of dihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, and triazolyl,
Among the first generally preferred subgroup of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, the following compounds are particularly preferred:
(R)-2-{2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-6-{4-[2-(2-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one;
(R)-2-[2-(4-imidazol-1-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2xe2x80x2-methyl-[2,4xe2x80x2]bithiazolyl-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;
(R)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-phenoxy)-ethylamino]-ethanol
(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;
(R)-1-pyridin-3-yl-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;
(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol; and
(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol.
Among the first generally preferred subgroup of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, the following compounds are especially preferred:
(R)-2-{2-[4-(ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;
(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;
(R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;
(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol; and
(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol.
A second generally preferred subgroup of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, comprises those compounds wherein Ar is phenyl; R is xe2x80x94NR9SO2R10; R1 is hydrogen, hydroxy, or halogen; R2, R3, R4, and R8, are hydrogen; X is oxygen and Y is a direct bond; and R5 is a five- or six-membered ring heterocycle selected from the group consisting of dihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, and triazolyl.
Among the second generally preferred subgroup of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, the following compounds are particularly preferred:
(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide; and
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide.
Among the second generally preferred subgroup of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, the following compounds are especially preferred:
(R)-N-[2-chloro-5-(2-{4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(2-{4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-(4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;
(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;
(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; and
(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-sulfonamide.
The instant invention further provides certain amine intermediates useful in the preparation of the compounds of Formula (I) which amine intermediates comprise compounds having the structural formula 
and the acid addition salts thereof, wherein:
R5 is a 5- or 6-membered ring heterocycle selected from the group consisting of isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazolyl, pyridazinyl, thiadiazolyl, thiazolinyl, thiazolyl, and triazinyl;
R6 and R7 are, independently, hydrogen, halogen, cyano, oxo, xe2x80x94(C1-C6)acyl, xe2x80x94CO2R9, xe2x80x94NR9R10, hydroxy, xe2x80x94(C1-C6)alkoxy, xe2x80x94CONR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, or xe2x80x94SO2R9; xe2x80x94(C1-C6)alkyl, optionally substituted with xe2x80x94(C3-C8)cycloalkyl, halogen, aryl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)haloalkyl, alkylalkoxy, hydroxy, xe2x80x94NR9R10, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, xe2x80x94SO2R9, or heterocycle; xe2x80x94(C3-C8)cycloalkyl, optionally substituted with xe2x80x94(C1-C6)alkyl, xe2x80x94(C3-C8)cycloalkyl, halogen, aryl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)haloalkyl, alkylalkoxy, hydroxy, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, xe2x80x94SO2R9, or heterocycle; aryl, optionally substituted with xe2x80x94(C1-C6)alkyl, xe2x80x94(C3-C7)cycloalkyl, halogen, aryl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)haloalkyl, alkylalkoxy, hydroxy, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, xe2x80x94SO2R9, or heterocycle; or heterocycle, optionally substituted with xe2x80x94(C1-C6)alkyl, xe2x80x94(C3-C8)cycloalkyl, halogen, aryl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C1-C6)haloalkyl, alkylalkoxy, hydroxy, xe2x80x94NR9R10, xe2x80x94NR9SO2R10, xe2x80x94SO2NR9R10, xe2x80x94SO2R9, or heterocycle;
R8 is hydrogen, xe2x80x94(C1-C4)alkyl, or halogen; and
Y is a direct bond, or xe2x80x94CH2xe2x80x94.
Generally preferred amine intermediates of the structural formula shown hereinabove comprise those compounds selected from the group consisting of:
2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamine;
2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamine;
2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamine;
2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamine;
2-[4-(4-ethyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;
2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamine;
2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamine;
2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamine;
2-(3-methyl-4-oxazol-4-yl)-phenoxy]-ethylamine;
2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamine;
2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamine;
2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamine;
2-[4-(2xe2x80x2-methyl-[2,4xe2x80x2]bithiazolyl-4-yl)-phenoxy]-ethylamine;
2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamine;
2-(4-[1,3,5]oxadiazol-2-yl-phenoxy)-ethylamine;
2-(4-oxazol-2-yl-phenoxy)-ethylamine;
2-(4-oxazol-4-yl-phenoxy)-ethylamine;
2-(4-oxazol-5-yl-phenoxy)-ethylamine;
2-[4-(2-phenethyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamine;
2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamine;
2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamine;
2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-(4-pyrazol-1-yl-phenoxy)-ethylamine;
2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamine;
2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamine;
2-4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamine;
2-(4-[1,2,3]thiazol-5-yl-phenoxy)-ethylamine;
2-(4-thiazol-2-yl-phenoxy)-ethylamine;
2-(4-thiazol-4-yl-phenoxy)-ethylamine;
2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamine;
2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamine;
2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamine;
2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamine; and
2-[4-(5-trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]-ethylamine; and the acid addition salts thereof.
The compounds and intermediates of the present invention may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts) nomenclature systems.
The carbon atom content of the various hydrocarbon-containing moieties may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e. the prefix (Ca-Cb) indicates a moiety of the integer xe2x80x9caxe2x80x9d to xe2x80x9cbxe2x80x9d carbon atoms, inclusive. Thus, for example, (C1-C3)alkyl refers to alkyl of one to three carbon atoms inclusive, or methyl, ethyl, propyl, isopropyl, and all isomeric forms, and straight and branched chain forms thereof.
The term xe2x80x9calkylxe2x80x9d denotes a straight or branched chain hydrocarbon. Representative examples of alkyl groups comprise methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, and hexyl.
The term xe2x80x9calkoxyxe2x80x9d denotes an alkyl group bonded to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d denotes a radical derived from chlorine, fluorine, bromine, or iodine.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. It is also possible for the cycloalkyl group to have one or more double or triple bonds, or a combination of double bonds and triple bonds, but is not aromatic. Examples of cycloalkyl groups having a double or triple bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclobutadienyl, and the like. It is also noted that the term cycloalkyl includes polycyclic compounds such as bicyclic or tricyclic compounds.
The term xe2x80x9cacylxe2x80x9d denotes a group derived from an organic acid (xe2x80x94COOH) by removal of of the hydroxy group (xe2x80x94OH).
The term xe2x80x9carylxe2x80x9d denotes a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl, naphthyl, and biphenyl. The aryl group can be substituted or unsubstituted.
The term xe2x80x9cheteroatomxe2x80x9d includes oxygen, nitrogen, sulfur, and phosphorus.
The term xe2x80x9cheterocyclexe2x80x9d, as employed within the definitions of R5, R6, R7, R9, and R10, denotes a cyclic, aromatic or non-aromatic hydrocarbon radical in which between one and four of the carbon atoms therein have been replaced with heteroatoms. If the heterocyclic radical contains more than one heteroatom, the individual heteroatoms may be the same or different. Representative examples of five- and six-membered aromatic, or non-aromatic, heterocyclic groups include chromenyl, dihydropyridazinonyl, dihydropyridazinyl, furyl, imidazolidinyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazolyl, pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl, and xanthenyl. It is to be understood that the heterocyclic radical may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term xe2x80x9cpyridylxe2x80x9d includes 2-, 3-, or 4-pyridyl, and the term xe2x80x9cthienylxe2x80x9d includes 2-, or 3-thienyl.
Specific representative examples of five- to six-membered aromatic, or non-aromatic, heterocyclic groups are 1,4-dioxanyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,3-dioxolanyl, 1,4-dithianyl, 1,2-dithiolyl, 1,3-dithiolyl, 2-imidazolinyl, 2H-imidazolyl, o-isoxazinyl, p-isoxazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl, 5H-1,2,5-oxathiazolyl, 3H-1,2-oxathiolyl, 1,3-oxathiolyl, 2H-pyranyl, 4H-pyranyl, 2-pyrazolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1,3,4-thiadiazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and 1,3,5-trithianyl.
It is also noted that the heterocyclic radical can comprise more than one ring. For example, a naphthyl group is a representative of a fused bicyclic ring system. It is also intended that the present invention include ring groups that have bridging atoms, or ring groups having a spiro-orientation. For example, the term xe2x80x9cspirocycloalkylxe2x80x9d means a cycloalkyl ring having a spiro union (the union formed by a single atom which is the only common member of the rings). In addition, it is understood that, unless specifically noted otherwise, all suitable isomers of the cyclic ring groups are included herein.
Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated, or fully unsaturated five- and/or six-membered rings, taken independently, optionally having one to four heteroatoms are anthranilyl, benzimidazolyl, benzofuryl, 2H-1-benzopyranyl, benzothiazolyl, benzo[b]thienyl, benzo[c]thienyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl, 4H-1,4-benzoxazinyl, benzoxazolyl, cinnolinyl, cyclopenta[b]pyridinyl, decalinyl, indazolyl, indenyl, indolinyl, indolizinyl, indolyl, 1H-indoxazinyl, isobenzofuryl, isoindenyl, isoindolyl, isoquinolinyl, naphthyl, naphthyridinyl, phthalazinyl, 1,8-pteridinyl, purinyl, pyrano[3,4-b]pyrrolyl, pyrido[3,2-b]-pyridinyl, pyrido[3,4-b]-pyridinyl, pyrido[4,3-b]-pyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, and tetralinyl.
The term xe2x80x9csubstitutedxe2x80x9d means that a hydrogen atom on a molecule has been replaced with a different atom or molecule. The atom or molecule replacing the hydrogen atom is denoted as a xe2x80x9csubstituent.xe2x80x9d
The phrase xe2x80x9ctherapeutically effective amountxe2x80x9d means an amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, which amount attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or prevents or delays the onset of one or more symtoms of a particular disease, condition, or disorder.
The term xe2x80x9cmammalxe2x80x9d means animals including, for example, dogs, cats, cows, sheep, horses, and humans. Preferred mammals include humans, including members of both male and female sexes.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
The terms xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d, or xe2x80x9ctreatmentxe2x80x9d embrace both preventative, i.e., prophylactic, and palliative treatment.
In another aspect of the instant invention, the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, can be employed in combination with an anti-obesity agent.
The anti-obesity agent is preferably selected from the group consisting of an apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, an MCR-4 agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotoninergic agent (such as fenfluramine or dexfenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, leptin (the OB protein), a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor (such as tetrahydrolipstatin, i.e. orlistat), an anorectic agent (such as a bombesin agonist), a Neuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor (such as Axokine), and human agouti-related protein (AGRP). Other anti-obesity agents, including the preferred agents set forth hereinbelow, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
Especially preferred anti-obesity agents comprise those compounds selected from the group consisting of orlistat, sibutramine, fenfluramine, dexfenfluramine, bromocriptine, phentermine, ephedrine, leptin, phenylpropanolamine, and pseudoephedrine.
Representative anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, phentermine can be prepared as described in U.S. Pat. No. 2,408,345; sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; fenfluramine and dexfenfluramine can be prepared as described in U.S. Pat. No. 3,198,834; and bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; and orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143, 5,420,305, 5,540,917, and 5,643,874.
The present invention further provides methods of treating xcex23 adrenergic receptor-mediated diseases, conditions, or disorders in a mammal in need of such treatment which methods comprise administering to the mammal a therapeutically effective amount of a compound of Formula (I), or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug; a combination of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and an anti-obesity agent; a pharmaceutical composition comprising an effective amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent; or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent, and an anti-obesity agent.
Preferably, the xcex23 adrenergic receptor-mediated disease, condition, or disorder is selected from the group consisting of obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, Crohn""s Disease, proctitis, asthma, intestinal motility disorder, ucler, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, and airway inflammatory disorder.
The invention further provides methods of increasing the lean meat content in edible animals which methods comprise administering to the edible animal a lean meat increasing amount of a compound of Formula (I), a stereoisomer, or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug; a pharmaceutical composition comprising a lean meat increasing amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent; or a pharmaceutical composition comprising a lean meat increasing amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent, and an anti-obesity agent.
The compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, can be administered to a patient at dosage levels in the range of from about 0.01 to about 1,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of from about 0.01 to about 300 mg is typically sufficient. However, some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered and the like. The determination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure. It is also noted that the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.
The dosage of the anti-obesity agent will also be generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired. In general, the dosage range of the anti-obesity agent is generally in the range of from about 0.001 to about 100 mg/kg body weight of the individual per day, preferably from about 0.1 to about 10 mg/kg body weight of the individual per day. However, some variability in the general dosage range may also be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered and the like. The determination of dosage ranges and optimal dosages for a particular patient is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.
According to the methods of the invention, a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug; or a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and an anti-obesity agent is administered to a subject in need of treatment therewith, preferably in the form of a pharmaceutical composition. In the combination aspect of the invention, the compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and the anti-obesity agent may be administered either separately or in the pharmaceutical composition comprising both. It is generally preferred that such administration be oral. However, if the subject being treated is unable to swallow, or oral administration is otherwise impaired or undesirable, parenteral or transdermal administration will be appropriate.
According to the methods of the invention, when the compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug; or a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and an anti-obesity agent are administered together, such administration can be sequential in time or simultaneous with the simultaneous method being generally preferred. For sequential administration, the compound of Formula (I), the stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the stereoisomer or prodrug and the anti-obesity agent can be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous. When the compound of Formula (I), the stereoisomer or prodrug thereof, or the pharmaceutically acceptable salt of the stereoisomer or prodrug, and the anti-obesity agent are administered sequentially, the administration of each can be by the same or by different methods.
According to the methods of the invention, the compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug; or a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and an anti-obesity agent is preferably administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier, vehicle, or diluent. Accordingly, the compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug; or a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and an anti-obesity agent can be administered to a patient separately or together in any conventional oral, rectal, transdermal, parenteral, (for example, intravenous, intramuscular, or subcutaneous) intracisternal, intravaginal, intraperitoneal, intravesical, local (for example, powder, ointment or drop), or buccal, or nasal, dosage form.
Compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of microorganism contamination of the compositions can be accomplished with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged adsorption of injectable pharmaceutical compositions can be brought about by the use of agents capable of delaying adsorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary pharmaceutical excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, as for example, paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and/or (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be used as fillers in soft or hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compound, may further comprise suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity thereby releasing the active component.
Dosage forms for topical administration of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs; and the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs and the anti-obesity agents, may comprise ointments, powders, sprays and inhalants. The active agent or agents are admixed under sterile condition with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required. Opthalmic formulations, eye ointments, powders, and solutions are also intended to be included within the scope of the present invention.
The following paragraphs describe exemplary formulations, dosages, etc. useful for non-human animals. The administration of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs; and the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs and the anti-obesity agents, can be effected orally or non-orally, for example, by injection.
An amount of a compound of Formula (I), or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug; or a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug and an anti-obesity agent, is administered such that an effective dose is received, generally a daily dose which, when administered orally to an animal is usually between about 0.01 and about 1,000 mg/kg of body weight, preferably between about 0.01 and about 300 mg/kg of body weight.
Conveniently, the compound can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply. The compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).
Conveniently, the compound can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate. A premix or concentrate of the compound in a carrier is more commonly employed for the inclusion of the agent in the feed. Suitable carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly employed in poultry feeds. A particularly effective carrier is the respective animal feed itself; that is, a small portion, of such feed. The carrier facilitates uniform distribution of the compound in the finished feed with which the premix is blended. It is important that the compound be thoroughly blended into the premix and, subsequently, the feed. In this respect, the compound may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier. It will be appreciated that the proportions of compound in the concentrate are capable of wide variation since the amount of active compound in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of compound.
High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements, which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound of the present invention. The mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.
If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the compound across the top of the dressed feed.
Drinking water and feed effective for increasing lean meat deposition and for improving lean meat to fat ratio are generally prepared by mixing a compound of the invention with a sufficient amount of animal feed to provide from about 10xe2x88x923 to 500 ppm of the compound in the feed or water.
The preferred medicated swine, cattle, sheep and goat feed generally contain from 1 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed.
The preferred poultry and domestic pet feeds usually contain about 1 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.
For parenteral administration in animals, the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought.
In general, parenteral administration involves injection of a sufficient amount of a compound of the present invention to provide the animal with 0.01 to 20 mg/kg/day of body weight of the active ingredient. The preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is in the range of from 0.05 to 10 mg/kg/day of body weight of active ingredient.
Paste formulations can be prepared by dispersing the active compound in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
Pellets containing an effective amount of a compound, pharmaceutical composition, or combination of the present invention can be prepared by admixing a compound of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal""s body.
The present invention has several advantageous veterinary features. For the pet owner or veterinarian who wishes to increase leanness and/or trim unwanted fat from pet animals, the instant invention provides the means by which this may be accomplished. For poultry and swine breeders, utilization of the method of the present invention yields leaner animals which command higher sale prices from the meat industry.
The terms pharmaceutically acceptable salts, esters, amides, or prodrugs mean the carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of a compound that are, within the scope of sound medical judgment, suitable for use with patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
The term xe2x80x9csaltsxe2x80x9d refers to inorganic and organic salts of a compound of Formula (I), or a stereoisomer, or prodrug thereof. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a compound Formula (I), or a stereoisomer or prodrug thereof with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, besylate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).
The term xe2x80x9cprodrugxe2x80x9d means a compound that is transformed in vivo to yield a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C1-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,Nxe2x80x94(C1-C2)alkylamino(C2-C3)alkyl (such as xcex2-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
Similarly, if a compound of Formula (I), or a stereoisomer thereof, comprises an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, Nxe2x80x94(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, xcex1-amino(C1-C4)alkanoyl, arylacyl and xcex1-aminoacyl, or xcex1-aminoacyl-xcex1-aminoacyl, where each xcex1-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, xe2x80x94P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
If a compound of Formula (I), or a stereoisomer thereof, incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRRxe2x80x2-carbonyl where R and Rxe2x80x2 are each independently (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural xcex1-aminoacyl or natural xcex1-aminoacyl-natural xcex1-aminoacyl, xe2x80x94C(OH)C(O)OY wherein Y is H, (C1-C6)alkyl or benzyl, xe2x80x94C(OY0)Y1 wherein Y0 is (C1-C4) alkyl and Y1 is (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N- or di-N,Nxe2x80x94(C1-C6)alkylaminoalkyl, xe2x80x94C(Y2)Y3 wherein Y2 is H or methyl and Y3 is mono-N- or di-N,Nxe2x80x94(C1-C6)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.
The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
The compounds of Formula (I) may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
It is also possible that the compounds of Formula (i) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, all of the tautomeric forms of the imidazole moiety are included in the invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included in the invention.
It is also intended that the invention disclosed herein encompass compounds of Formula (I) that may be synthesized in vitro using laboratory techniques, such as those well known to the synthetic organic chemist of ordinary skill, or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also intended that the compounds of Formula (I) may be synthesized using a combination of in vitro and in vivo techniques.
The present invention also embraces isotopically-labelled compounds of Formula (I), which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. The compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, or prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are intended to be within the scope of this invention.
Certain isotopically-labelled compounds of Formula (I), for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in compound and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) can generally be prepared by carrying out the procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an isotopically labelled reagent for a non-isotopically labelled reagent.
The compounds of Formula (I) may be prepared by processes which include those known, or those analogous to those known, in the chemical arts. Such processes for the preparation of the compounds of Formula (I) as defined hereinabove are illustrated according to the exemplary synthetic sequences set forth hereinbelow in Schemes I through III. Furthermore, Schemes IV through VI illustrate exemplary synthetic routes to the intermediates useful in the production of the compounds of Formula (I). Unless otherwise qualified, the meanings of the generic radicals are as indicated hereinabove.
In the synthetic sequence designated Scheme I, an appropriately substituted oxirane derivative (III) is condensed with an appropriately substituted amine (II) to produce a compound of Formula (I).
The amine derivatives (II) may be conveniently prepared as depicted in general Schemes IV, V, and VI hereinbelow, however, other methods of preparing such amine derivatives will be known to one of ordinary skill in the art having benefit of the teachings of the instant disclosure.
The oxirane derivatives (III) may be prepared according to known methods, including those set forth in, for example, U.S. Pat. Nos. 5,541,197, 5,561,142, 5,705,515, and 6,037,362, the disclosures of which are all incorporated herein by reference. Where available, such oxirane derivates may also be obtained from commercial sources. 
The condensation of oxirane (III) and amine (II) is most conveniently performed at an elevated temperature in a polar, protic solvent, for example, an alcohol such as methanol or ethanol. Alternatively, a co-solvent system may also be employed, for example, by adding a polar, aprotic co-solvent such as dimethylsulfoxide to the protic solvent. Isolation and purification of the compound of Formula (I) thus formed may then be effected according to known methods. An example of such condensation and purification is disclosed hereinbelow in the general preparative method denoted Method A.
Alternatively, as depicted in Scheme II, the compounds of Formula (I) may also be prepared by condensing an appropriately substituted protected alcohol (IV) with an amine (II). The protected alcohol (IV) incorporates a suitable leaving group that is susceptible to displacement by nucleophilic attack of the nitrogen atom of amine (II). Suitable leaving groups that may be employed in protected alcohol (IV) may comprise, for example, mesylates, tosylates, and nosylates, or halides, for example, chlorides, bromides, or iodides. The protected alcohol derivatives (IV) may be prepared according to known methods, including, for example, those methods disclosed in commonly-assigned U.S. Pat. No. 6,008,361, the disclosure of which is hereby incorporated by reference. However, other methods of preparing such protected alcohols will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art. See, for example, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, (1991), and the references cited therein. 
The condensation of protected alcohol (IV) and amine (II) is typically effected in the presence of an appropriate, sterically-hindered base, for example, N,N-diisopropylethylamine (Hunig""s Base) in a polar, aprotic solvent, such as dimethylsulfoxide, at elevated temperature. The protected amino alcohol (V) thus formed may then be deprotected according to well-known preparative methods, for example, where (V) is a silylated derivative, preferably by treatment with tetrabutylammonium fluoride. An example of such condensation and deprotection is disclosed hereinbelow in the general preparative method denoted as Method B.
Alternatively, as shown in Scheme III, the compounds of Formula (I) may also be prepared by dehalogenation of a compound of Formula (Ia), wherein the Ar group represents an appropriately substituted 6-chloropyridine derivative. 
The dehalogenation of the above-mentioned 6-chloropyridine derivative (Ia) may be effected according to known methods. Most conveniently, such dehalogenation is performed using a metal catalyst, preferably palladium on carbon, in a polar solvent, such as methanol. The reaction is preferably conducted at room temperature over a period of several hours, i.e. overnight. Other methods of effecting dehalogenation reactions of this kind will be known to one of ordinary skill in the art. An example of such dehalogenation reaction is disclosed hereinbelow in the general preparative method denoted Method C.
With reference to Schemes I and II, the aforementioned amine derivatives of formula (II) may be prepared according to the exemplary synthetic sequences depicted hereinbelow in Schemes IV, V, and VI. It is to be understood, however, that such examples are offered for purposes of illustration of these embodiments of the instant invention and are not to be construed in any manner as limitations thereof, as other methods of preparing such amine derivatives will be known, or apparent, to one of ordinary skill in the art having benefit of the instant disclosure. 
General Scheme IV hereinabove depicts a convenient, exemplary synthetic route to amine derivatives (II) in which an appropriately substituted anisole derivative (VI) serves as the synthetic platform upon which the heterocyclic moiety R5 may be constructed. Such anisole derivatives will be well known to one of ordinary skill in the art and may either be prepared according to known methods or obtained commercially. The anisole derivatives (VI) may be functionalized as illustrated hereinbelow in Schemes IVa to IVc to produce heteroaryl derivatives (VII). Although general Scheme IV, and the synthetic schemes related thereto that are shown below, depict the use of an anisole derivative (VI), it is to be understood that an appropriately substituted phenol derivative may also be employed in place of the anisole derivative, where such phenol is chemically compatible with other functional groups and/or reagents that may be present or utilized in subsequent synthetic steps. The heteroaryl derivatives (VII) so produced are then demethylated, for example, with methanesulfonic acid or boron tribromide, to form an appropriately substituted phenol derivative (VIII). The phenol derivative (VIII) so produced is then coupled with a protected amino alcohol to form the amine-protected derivative (IX). An example of such coupling reaction is provided hereinbelow in Example 1. The ability to select an appropriate amine-protecting group to form the amine-protected alcohol (IX) is well within the purview of one of ordinary skill in the art. For examples of typical amine protecting groups, see, for example, T. W. Greene, supra, and the references cited therein. The coupling reaction between the phenol derivative (VIII) and the amine-protected derivative (IX) may be effected according to methodologies that will be well-known to one of ordinary skill in the art, however, such coupling is preferably effected via a so-called Mitsunobu reaction. This reaction is typically performed with stirring at room temperature (or at elevated temperature if required) in the presence of a dehydrating agent, for example, a stoichiometric amount of a diazocarboxyl compound, such as 1,1xe2x80x2-(azodicarbonyl)-dipiperidine (ADDP), and a phosphine, for example, triphenylphosphine. The reaction can be carried out in any reaction-inert solvent such as tetrahydrofuran, dimethylformamide, or a hydrocarbon, or halogenated hydrocarbon solvent. The amine-protected derivative (IX) so formed is then deprotected in a conventional manner, for example, by treatment with methanesulfonic acid, or various other deprotecting agents under conditions that will be well known to one of ordinary skill in the art, including hydrogenoloysis in the presence of a suitable metal catalyst, such as palladium on carbon in an inert solvent. The hydrogenolysis reaction is typically effected anywhere from room temperature up to about 90xc2x0 C. An example of such a deprotection reaction is provided hereinbelow in Example 2.
The following specific schemes, designated Schemes IVa to IVe, exemplify the syntheses of various synthetic precursors to the various amine derivatives (II) depicted in Schemes I, II, and IV wherein the heterocyclic moiety R5 is as shown hereinbelow. As before, it is to be understood that these examples are offered for purposes of illustration, and not of limitation. 
The thiazole, oxazole, and imidazole-functionalized anisole derivatives (VIIa) may be produced according to the exemplary route depicted in Scheme IVa, beginning with an appropriately substituted thioamide, amide, or amidine derivative (VIa). Such thioamide, amide, or amidine derivatives will be well known to one of ordinary skill in the art and may either be obtained commercially or prepared by known preparative methods. The thioamide, amide, or amidine derivative (VIa) is cyclized with an appropriate xcexc-bromoketone to form the desired derivative (VIIa). Such xcex1-bromoketones will also be well known to one skilled in the art and may also be obtained commercially or prepared by one of ordinary skill in the art according to known methods. 
Alternatively, regioisomeric thiazole, oxazole, and imidazole derivatives (VIIb) can be synthesized according to the exemplary synthetic route shown in Scheme IVb. In Scheme IVb, an appropriately substituted acylated anisole derivative (VIb) is xcex1-halogenated, preferably xcex1-brominated, according to conventional methods, for example, by the reaction of (VIb) with tetrabutylammonium tribromide (TBABBr3), or dibromobarbituric acid (DBBA). The substituted xcex1-bromoketone (VIbxe2x80x2) so produced is then condensed with an appropriate thioamide, amide, or amidine derivative to form the thiazole, oxazole, or imidazole derivative (VIIb). Such condensation may be effected neat, or, preferably, in the presence of a polar solvent, such as an alcohol, or a halogenated hydrocarbon, such as chloroform. 
The intermediate isoxazole or pyrazole derivatives (VIIc) may be synthesized according to the exemplary route depicted in Scheme IVc. In Scheme IVc, an acylated anisole derivative (VIc) is reacted with an appropriately substituted ester and a crown ether, for example, 18-crown-6, in the presence of an organic base, such as potassium tert-butoxide, in a non-protic solvent, such as tetrahydrofuran, at elevated temperature. The diketo derivative (VIcxe2x80x2) thus formed is then cyclized with an appropriately substituted hydrazine derivative or hydroxylamine in a polar solvent, such as ethanol, at elevated temperature to produce pyrazole derivative (VIIc), and the regioisomer thereof (VIIcxe2x80x2). 
The intermediate isoxazole or pyrazole derivatives (VIId) may be synthesized according to the exemplary route depicted in Scheme IVd. In Scheme IVd, an appropriately substituted diketo derivative (IVd) is condensed with an appropriately substituted hydrazine derivative or hydroxylamine to furnish phenol derivatives (VIId). The intermediate diketo derivative (VId) may be obtained from commercial sources or prepared according to known methods. The condensation reaction is preferably effected in a polar solvent, such as ethanol, at elevated temperature. An exemplary preparation of a compound of formula (VIId) is provided in Example 35 hereinbelow. 
The intermediate imidazole derivatives (VIIe) or pyrazole derivatives (VIIexe2x80x2) may be prepared as outlined hereinabove in exemplary Scheme (IVe). As depicted in Scheme (IVe), an appropriately substituted boronic acid derivative (VIe) is reacted with an appropriately substituted imidazole or pyrazole derivative in the presence of a suitable catalyst, preferably copper (II) acetate, in a halogenated hydrocarbon solvent, preferably dichloromethane, to form imidazole derivative (VIIe) or pyrazole derivative (VIIexe2x80x2) respectively. The boronic acid derivatives (VIe), as well as the appropriately substituted imidazole or pyrazole derivatives, may be either obtained commercially or prepared according to known methods. An exemplary preparation of a compound of formula (VIIexe2x80x2) is provided in Example 30 hereinbelow. 
Scheme V hereinabove depicts an exemplary, alternative route to a formula (II) amine beginning with an appropriately substituted fluorobenzene derivative (X). Such fluorobenzene derivatives (X) may be obtained commercially, or, in the alternative, may be prepared by known methods. The fluorobenzene derivative (X), which serves as a synthetic scaffold from which the heterocyclic moiety R5 is assembled, is reacted with an appropriately functionalized amino alcohol to furnish amine (II). The reaction between the amino alcohol and the fluorobenzene derivative (XI) is typically effected in a polar, aprotic solvent, preferably dimethylsulfoxide, at an elevated temperature in the presence of an organic or inorganic base, preferably potassium tert-butoxide. A representative synthesis of an amine (II) as depicted in Scheme V is provided hereinbelow in Examples 28 and 29. 
Scheme Va above illustrates a convenient, generally applicable synthetic approach to the heterocyclic amine precursor of formula (XI) shown in Scheme V, wherein R5 represents a pyridazin-3-one moiety. Here, the fluorobenzene starting material (Xa) is condensed with hydrazine hydrate in a polar, protic solvent, such as ethanol, at elevated temperature, to form amine precursor (XIa). An exemplary synthesis of precursor (XIa) as shown in Scheme Va is disclosed hereinbelow in Example 28. 
A generally applicable, alternative synthesis of an amine intermediate (II) is shown in Scheme VI beginning with protected amine (XII). The protected amine (XII), which may be prepared by known methods, is functionalized so as to form amine (IX) which subsequently serves as a synthetic basis for the preparation of protected amine (IX) which incorporates the substituted heterocyclic moiety R5. Representative preparations of such heterocyclic moieties are illustrated hereinbelow in Schemes VIa to VId. Typically, the protected amine starting material (XII), wherein X is a direct bond, is prepared by appropriate derivatization of a commercially available phenalkylamine starting material. An example of such derivatization is disclosed hereinbelow in Example 11. Where X represents oxygen, such protected amine derivatives (XII) are typically derived from an aforementioned Mitsunobu coupling reaction between an appropriately substituted, commercially available phenol and an ethanolamine derivative. An example of such a coupling reaction is provided hereinbelow in Example 20. 
In Scheme VIa, the amine-protected derivative (XIIa) is acylated under standard Friedel-Crafts reaction conditions to form the acyl derivative (XIIaxe2x80x2). Such acylation will be well known to one of ordinary skill in the art and is typically effected by treating (XIIa) with an appropriately substituted acyl chloride in the presence of a Lewis acid, i.e. aluminum (III) chloride in a reaction-inert solvent, such as dichloromethane or similar halogenated hydrocarbon solvent at, or below, room temperature. The acylated derivate (XIIa) so produced is then xcex1-halogenated relative to the keto group of the acyl moiety to form xcex1-haloketone (XIIaxe2x80x3). Such xcex1-halogenation, preferably xcex1-bromination, may be effected according to conventional methods, preferably by the reaction of (XIIa) with tetrabutylammonium tribromide (TBABBr3), or dibromobarbituric acid (DBBA). An example of such an xcex1-bromination reaction is provided hereinbelow in Example 21. The preferred xcex1-bromoketone (XIIaxe2x80x3) so produced is then condensed with an appropriate thioamide, amide, or amidine derivative to form a protected thiazole, oxazole, or imidazole derivative (IXa) respectively. Although the condensation reaction may be effected in the absence of a solvent, i.e. neat, for purposes of product purity and ease in reaction work-up and purification, it is generally preferred that the condensation reaction be performed in a reaction-inert solvent, including, for example, ethanol, chloroform, or similar solvent. An example of such condensation reaction is provided in Example 22 hereinbelow. The protected amine derivative (IXa) so produced may then be deprotected according to the methodologies described hereinabove in Scheme IV. An example of such deprotection reaction is provided hereinbelow in Example 23. 
The protected triazole derivatives (IXb) shown in Scheme VIb may be produced by reaction of an amine-protected amide derivative (XIIb) with an appropriately substituted dimethylaminodimethylacetal at elevated temperature under neat conditions followed by treatment with hydrazine hydrate in glacial acetic acid, also at elevated temperature. The protected amine derivative (IXb) thus formed may then be deprotected as shown and described hereinabove in Scheme IV. 
The oxadiazole derivatives (IXc) shown in Scheme VIc may be synthesized by reacting an appropriately substituted hydrazide (XIIc) with an acyl chloride under standard conditions, i.e., in the presence of a base, preferably an organic base such as triethylamine, in a reaction-inert solvent such as dichloromethane. If necessary, the resulting diacyl hydrazide intermediate may then be treated with a cyclizing agent, such as triflic anhydride, to effect ring closure. The protected amine derivative (IXc) thus produced may then be deprotected as shown and described hereinabove in Scheme IV. An exemplary synthetic sequence, which illustrates the preparation of a protected amine derivative (IXc), as well as the subsequent deprotection thereof, is provided in Examples 24 to 27 hereinbelow, wherein Y represents xe2x80x94CH2xe2x80x94. 
The protected thiazole, oxazole, or imidazole derivates (IXd) depicted in Scheme VId may be prepared beginning with nitrile (XIId). Typically, nitrile (XIId) is prepared via the aforementioned Mitsunobu coupling reaction between commercially available phenol and ethanolamine derivatives. Reduction of nitrile (XIId) with, for example, a metal hydride such as diisobutylaluminum hydride (DIBAL-H) in a reaction-inert, hydrocarbon solvent such as toluene or hexanes, or a halogenated hydrocarbon solvent such as dichloromethane furnishes aldehyde (XIIdxe2x80x2). The aldehyde (XIIdxe2x80x2) so produced is then xcex1-halogenated to form xcex1-haloaldehyde (XIIdxe2x80x3). Such xcex1-halogenation is preferably effected as set forth hereinabove in Scheme VIa. The preferred xcex1-bromoaldehyde (XIIaxe2x80x3) is then condensed with an appropriate thioamide, amide, or amidine derivative to form the protected thiazole, oxazole, or imidazole derivative (IXd), preferably also according to the method disclosed hereinabove in Scheme VIa. The protected amine derivative (IXd) so formed may then be deprotected as shown and described hereinabove in Scheme IV.
Conventional methods and/or techniques of separation and purification known to one of ordinary skill in the art can be used to isolate the compounds of Formula (I), as well as the various intermediates related thereto. Such techniques will be well-known to one of ordinary skill in the art and may include, for example, all types of chromatography (HPLC, column chromatography using common adsorbents such as silica gel, and thin-layer chromatography), recrystallization, and differential (i.e., liquid-liquid) extraction techniques.
Chemical Syntheses
The embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.